The invention relates to the preparation of sulfonyl pyrazoles useful as anti-inflammatory/analgesic agents. It has now been found that the use of a metal fluoride salt allows processes of preparing sulfonyl pyrazoles containing versatile amino, ether, or thio ether component on the 5-position of the pyrazole ring to be performed at lower temperature, such as room temperature, with consistent higher yields.
The sulfonyl pyrazoles prepared by the methods of the present invention are useful in the treatment of cyclooxygenase (COX) mediated diseases, such as arthritis, neurodegeneration and colon cancer, in mammals, preferably humans, dogs, cats or livestock. Two forms of COX are now known, a constitutive isoform (COX-1) and an inducible isoform (COX-2) of which expression is upregulated at sites of inflammation (Vane, J. R.; Mitchell, et. al., Proc. Natl. Acad. Sci. USA, 1994, 91, 2046). COX-1 appears to play a physiological role and to be responsible for gastrointestinal and renal protection. On the other hand, COX-2 appears to play a pathological role and is believed to be the predominant isoform present in inflammation conditions. Preferred compounds prepared by the methods of the present invention are selective COX-2 inhibitors. Therapeutic use of conventional COX inhibitors is limited due to drug associated side effects, including life threatening ulceration and renal toxicity. Compounds that selectively inhibit COX-2 would exert anti-inflammatory effects without the adverse side effects associated with COX-1 inhibition.
A variety of sulfonylpyrazoles that inhibit COX have been prepared by other methods described in patent publications WO 97/11704, WO 01/40216, EP 1104758, EP 1104759, and EP 1104760; and U.S. Non-Provisional patent application Ser. No. 09/798,752, filed Mar. 2, 2001, and U.S. Non-Provisional patent application Ser. No. 09/824,550, filed Apr. 2, 2001. None of these methods use a fluoride containing salt.
Filed simultaneously with the present application on Nov. 2, 2001, are United States Provisional Applications entitled xe2x80x9cHydrazinyl and Nitrogen Oxide Pyrazolesxe2x80x9d; xe2x80x9cHeterocyclo-Alkylsulfonyl Pyrazolesxe2x80x9d; xe2x80x9c5-Heteroatom-Substituted Pyrazolesxe2x80x9d; xe2x80x9c5-Heterocyclo-pyrazolesxe2x80x9d; and xe2x80x9c5-(Alkylidene-Cycloalkyl)- and 5-(Alkylidene-Heterocyclyl)-Pyrazolesxe2x80x9d, which refer to certain pyrazole COX-2 inhibitors that can be prepared by the present processes of the invention. The aforesaid applications are herein incorporated in their entireties by reference.
The present invention relates to a process for preparing a compound of formula I: 
or the pharmaceutically acceptable salts thereof;
wherein the ring of the formula (R5)-A-(SOmR4) is selected from the group consisting of 
m is 0, 1 or 2;
X is  greater than CR5 or  greater than N;
R1 is a radical selected from the group consisting of H, xe2x80x94NO2, xe2x80x94CN, (C1-C6)alkyl, (C1-C6)alkyl-SO2xe2x80x94, (C6-C10)aryl-SO2xe2x80x94, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94;
R2 is a radical selected from the group consisting of H, xe2x80x94NO2, xe2x80x94CN, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C6-C10)aryl, (C1-C9)heteroaryl, (C1-C9)heterocyclyl, (C1-C6)alkyl-Oxe2x80x94, (C3-C7)cycloalkyl-Oxe2x80x94, (C6-C10)aryl-Oxe2x80x94, (C1-C9)heteroaryl-Oxe2x80x94, (C1-C9)heterocyclyl-Oxe2x80x94, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C3-C7)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C7)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C9)heteroaryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C9)heterocyclyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C3-C7)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C7)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-NH, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, [(C3-C7)cycloalkyl]2-Nxe2x80x94, [(C6-C10)aryl]-NHxe2x80x94, [(C6-C10)aryl]2-Nxe2x80x94, [(C1-C6)alkyl]-[((C8-C10)aryl)-N]xe2x80x94, [(C1-C9)heteroaryl]-NHxe2x80x94, [(C1-C9)heteroaryl]2-Nxe2x80x94, [(C1-C9)heterocyclyl]-NHxe2x80x94, [(C1-C9)heterocyclyl]2-Nxe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90)xe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C3-C7)cycloalkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C3-C7)cycloalkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C9)heteroaryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C9)heteroaryl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C9)heterocyclyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Sxe2x80x94 and (C1-C6)alkyl optionally substituted by one xe2x80x94OH group or by one to four fluoro substituents;
R3 is a radical selected from the group consisting of 
R6 is a radical independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C8-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl, (C3-C8)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl;
R7 is a radical independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl, (C3-C8)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl; or
R6 and R7 may optionally be taken together with the nitrogen or the oxygen to which they are attached to form a 3- to 8-membered heterocyclic ring radical; wherein said 3- to 8-membered heterocyclic ring radical may optionally contain at least one nitrogen or one oxygen heteroatom in addition to said nitrogen or said oxygen to which R6 and R7 are attached;
wherein said 3- to 8-membered heterocyclic ring radical made up of R6 and R7 may optionally be substituted on any ring carbon atom by one to three substituents per ring independently selected from the group consisting of halo, xe2x80x94OH, (C1-C6)alkyl-Oxe2x80x94, and (C1-C6)alkyl optionally substituted by one to four fluoro moieties;
wherein said 3- to 8-membered heterocyclic ring radical made up of R6 and R7 may optionally be substituted on any ring carbon atom by at least one oxo or one (C1-C6)alkylidene substituent per ring;
R8 is a radical selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl, (C3-C8)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl; or
R7 and R8 may optionally be taken together with the nitrogen to which they are attached to form a 3- to 8-membered heterocyclic ring radical; wherein said 3- to 8-membered heterocyclic ring radical may optionally contain at least one nitrogen or one oxygen heteroatom in addition to said nitrogen to which R7 and R8 are attached;
wherein said 3- to 8-membered heterocyclic ring radical made up of R7 and R8 may optionally be substituted on any ring carbon atom by one to three substituents per ring independently selected from the group consisting of halo, xe2x80x94OH, (C1-C6)alkyl-Oxe2x80x94 and (C1-C6)alkyl optionally substituted by one to four fluoro moieties;
wherein said 3- to 8-membered heterocyclic ring radical made up of R7 and R8 may optionally be substituted on any ring carbon atom by at least one oxo or one (C1-C6)alkylidene substituent per ring;
wherein each of R6, R7, or R8 (C1-C6)alkyl radicals may optionally be substituted on any carbon atom by one to three substituents per (C1-C6)alkyl components independently selected from the group consisting of halo, xe2x80x94OH, (C1-C6)alkyl-Oxe2x80x94, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C6-C10)aryl, (C1-C9)heteroaryl, (C1-C10)heterocyclyl, xe2x80x94CN, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, (C6-C10)aryl-NHxe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94, (C1-C9)heteroaryl-NHxe2x80x94, (C1-C10)heterocyclyl-NHxe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Sxe2x80x94;
wherein each of R6, R7, or R8 (C6-C10)aryl, (C3-C8)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl ring radicals may optionally be substituted on any ring carbon atom by one to three substituents per ring independently selected from the group consisting of halo, xe2x80x94OH, (C1-C6)alkyl-Oxe2x80x94, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, xe2x80x94CN, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, (C6-C10)aryl-NHxe2x80x94, [(C1-C6)alkyl]-[(C6-C10)aryl]-Nxe2x80x94, (C1-C9)heteroaryl-NHxe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[(C6-C10)aryl]-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Sxe2x80x94, and (C1-C6)alkyl optionally substituted by one to four fluoro moieties;
wherein each of R6, R7, or R8 (C3-C8)cycloalkyl and (C1-C10)heterocyclyl radicals or substituents, respectively, may also optionally be substituted on any ring carbon atom by at least one oxo or one (C1-C6)alkylidene substituent or moiety, respectively, per ring;
R4 is a radical selected from the group consisting of xe2x80x94NH2, (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, [(C6-C10)aryl(C1-C6)alkyl]-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C6-C10)aryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94HCxe2x95x90Nxe2x80x94, [C1-C6)alkyl]2Nxe2x80x94HCxe2x95x90Nxe2x80x94, or [(C6-C10)aryl]-NHxe2x80x94HCxe2x95x90Nxe2x80x94, and and (C1-C6)alkyl optionally substituted by one to four xe2x80x94OH substituents; and
R5 is a radical selected from the group consisting of H, halo, xe2x80x94OH, (C1-C6)alkyl-Oxe2x80x94, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, xe2x80x94CN, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, (C6-C10)aryl-NHxe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94, (C1-C9)heteroaryl-NHxe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Sxe2x80x94, and, (C1-C6)alkyl optionally substituted by one to four fluoro substituents;
comprising reacting a compound of the formula II: 
wherein the ring of the formula (R5)-A-(SOmR4), m, and R1 through R5 are as defined above, and wherein R10 is a radical selected from the group consisting of halo, (C1-C6)alkyl-SO3xe2x80x94, (C6-C10)aryl-SO3xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, and (C6-C10)aryl-SO2xe2x80x94, wherein each of said (C1-C6)alkyl component of said (C1-C6)alkyl-SO3xe2x80x94 and (C1-C6)alkyl-SO2xe2x80x94 radicals is optionally substituted by one to six fluoro substituents;
with a compound of formula R3xe2x80x94H, wherein R3 is as defined above, in the presence of a fluoride containing salt; in the presence of a solvent.
The compounds prepared by the process of this invention include all stereoisomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e.g., R and S enantiomers), as well as racemic, diastereomeric and other mixtures of such isomers.
The compounds prepared by the process of this invention may also exist in different tautomeric forms. This invention relates to process to prepare all tautomers of formula I.
The compounds prepared by the process of this invention may contain olefin-like double bonds. When such bonds are present, the process of the invention prepares all compounds of formula I in cis and trans configurations and in mixtures thereof.
Unless otherwise indicated, the term xe2x80x9cfunctional groupxe2x80x9d refers to xe2x80x9cradicalxe2x80x9d, xe2x80x9csubstituentxe2x80x9d xe2x80x9cmoietyxe2x80x9d, or xe2x80x9csub-moietyxe2x80x9d, as defined below. The term xe2x80x9csub-functional groupxe2x80x9d refers to xe2x80x9csubstituentxe2x80x9d xe2x80x9cmoietyxe2x80x9d, or xe2x80x9csub-moietyxe2x80x9d, as defined below.
Unless otherwise indicated, the term xe2x80x9cradicalxe2x80x9d or xe2x80x9cradicalsxe2x80x9d refers to an individual member of a variable (R1, R2, R3 etc) of the compound of the formula I (e.g., R1 is a radical selected from the group consisting of H and (C1-C6)alkyl means that R1 can be either a H radical or a (C1-C6)alkyl radical).
Unless otherwise indicated, the term xe2x80x9csubstituentxe2x80x9d or xe2x80x9csubstituentsxe2x80x9d refers to a replacement of at least one atom of a radical, wherein the term xe2x80x9cradicalxe2x80x9d is as defined above, by another atom or group of atoms. For example, an (C1-C6)alkyl substituent may replace a hydrogen atom of R1 (C6-C10)aryl radical.
Unless otherwise indicated, the term xe2x80x9cmoietyxe2x80x9d or xe2x80x9cmoietiesxe2x80x9d refers to a replacement of at least one atom of a substituent, wherein the term xe2x80x9csubstituentxe2x80x9d is as defined above, by another atom or group of atoms. For example, an (C1-C6)alkyl moiety of a particular substituent (e.g., (C1-C6)alkyl, (C6-C10)aryl, or (C3-C8)cycloalkyl substituent) may replace a hydrogen atom of that substituent.
Unless otherwise indicated, the term xe2x80x9csub-moietyxe2x80x9d or xe2x80x9csub-moietiesxe2x80x9d refers to a replacement of at least one atom of a moiety, wherein the term xe2x80x9cmoietyxe2x80x9d is as defined above, by another atom or group of atoms. For example, an (C1-C6)alkyl sub-moiety of a particular moiety (e.g., (C1-C6)alkyl, (C6-C10)aryl, or (C3-C8)cycloalkyl moiety) may replace a hydrogen atom of that moiety.
Unless otherwise indicated, the term xe2x80x9c(C1-C6)alkylxe2x80x9d as well as the (C1-C6)alkyl component of other terms referred to herein (e.g., the xe2x80x9c(C1-C6)alkyl component of (C1-C6)alkyl-Oxe2x80x94), may be linear or branched (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, secondary-butyl, tertiary-butyl), wherein each of said (C1-C6)alkyl functional group, wherever they occur, may optionally be substituted by one to three sub-functional groups per (C1-C6)alkyl component independently selected from the group consisting of fluoro, xe2x80x94OH, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C1-C6)alkyl-Oxe2x80x94, oxo, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, xe2x80x94CN, xe2x80x94NO2, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, (C6-C10)aryl-NHxe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94, (C1-C9)heteroaryl-NHxe2x80x94, (C1-C10)heterocyclyl-NHxe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl, (C2-C9)heteroaryl, (C6-C10)aryl-Oxe2x80x94, (C1-C9)heteroaryl-Oxe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-S(xe2x95x90O)xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94(C1-C6)alkyl-NH and (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94.
Unless otherwise indicated, the term xe2x80x9c(C1-C6)alkyl radicals may optionally be substituted on any carbon atom by one to three substituents per (C1-C6)alkyl componentsxe2x80x9d refers to a replacement of at least one atom of any (C1-C6)alkyl components of any radicals containing an (C1-C6)alkyl component, wherein the term xe2x80x9cradicalxe2x80x9d is as defined above, by another atom or group of atoms. Radicals containing an (C1-C6)alkyl component include, but are not limited to, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, [(C1-C6)alkyl]-[((C6-C10)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Sxe2x80x94.
Unless otherwise indicated, the term xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo or iodo.
Unless otherwise indicated, the term xe2x80x9c(C2-C6)alkenylxe2x80x9d means straight or branched hydrocarbon chain functional groups of 2 to 6 carbon atoms having at least one double bond including, but not limited to ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, or 2-butenyl.
Unless otherwise indicated, the term xe2x80x9c(C1-C6)alkylidenexe2x80x9d refers to functional groups of the formula xe2x95x90CH2 or xe2x95x90(CHm)nCH3, wherein m is 0 to 2 and n is 1 to 5, such as methylidine (xe2x95x90CH2), ethylidine (xe2x95x90CHxe2x80x94CH3), propylidene (xe2x95x90CHxe2x80x94CH2CH3), or butylidene (xe2x95x90CHxe2x80x94CH2CH2CH3). Said (C1-C6)alkylidene functional groups may be branched such as 1-methyl-ethylidine (xe2x95x90C(CH3)xe2x80x94CH3).
Unless otherwise indicated, the term xe2x80x9c(C2-C6)alkynylxe2x80x9d is used herein to mean straight or branched hydrocarbon chain functional groups of 2 to 6 carbon atoms having one triple bond including, but not limited to, ethynyl (xe2x80x94Cxe2x89xa1Cxe2x80x94H), propynyl (xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94H or xe2x80x94Cxe2x89xa1Cxe2x80x94CH3), or butynyl (xe2x80x94CH2xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94H, or xe2x80x94CH2xe2x80x94Cxe2x89xa1Cxe2x80x94CH3, or xe2x80x94Cxe2x89xa1Cxe2x80x94CH2CH3).
Unless otherwise indicated, the term xe2x80x9c(C3-C7)cycloalkylxe2x80x9d refers to a mono or bicyclic carbocyclic ring functional groups including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl and bicyclo[5.2.0]nonanyl; wherein said (C3-C7)cycloalkyl functional groups may optionally contain 1 or 2 double bonds including, but not limited to, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
Unless otherwise indicated, the term xe2x80x9c(C6-C10)arylxe2x80x9d means aromatic functional groups such as phenyl, naphthyl, tetrahydronaphthyl, or indanyl, wherein said (C6-C10)aryl functional groups are optionally substituted on any ring carbon atom by one to two sub-functional groups per ring, wherein said substituents are independently selected from the group consisting of halo, xe2x80x94OH, xe2x80x94CN, xe2x80x94SH, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, xe2x80x94NO2, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C6-C10)aryl, (C1-C9)heteroaryl, (C1-C9(C1-C6)alkyl-Oxe2x80x94, xe2x80x94OCF3, (C1-C6)alkyl-Sxe2x80x94, (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, (C6-C10)aryl-NHxe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94, (C1-C9)heteroaryl-Nxe2x80x94, (C1-C10)heterocyclyl-NHxe2x80x94, H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94HNxe2x80x94(C1-C6)alkyl-NH, Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94.
Unless otherwise indicated, the term xe2x80x9c[(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94xe2x80x9d has the following structure: 
wherein the term xe2x80x9c(C1-C6)alkylxe2x80x9d and the term xe2x80x9c(C6-C10)arylxe2x80x9d are as defined above.
Unless otherwise indicated, the term xe2x80x9c[(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94xe2x80x9d has the following structure: 
wherein the term xe2x80x9c(C1-C6)xe2x80x9d and the term xe2x80x9c(C6-C10)xe2x80x9d are as defined above.
Unless otherwise indicated, the term xe2x80x9c(C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94HNxe2x80x94(C1-C6)alkyl-NHxe2x80x9d has the following structure: 
wherein the term xe2x80x9c(C1-C6)alkylxe2x80x9d is as defined above.
Unless otherwise indicated, the term xe2x80x9coxoxe2x80x9d refers to xe2x95x90O.
Unless otherwise indicated, the term xe2x80x9c[(C1-C6)alkyl]-NHxe2x80x94HCxe2x95x90Nxe2x80x94xe2x80x9d refers to 
wherein the term xe2x80x9c(C1-C6)alkylxe2x80x9d is as defined above
Unless otherwise indicated, the term xe2x80x9cC1-C6)alkyl]2Nxe2x80x94HCxe2x95x90Nxe2x80x94xe2x80x9d refers to 
wherein the term xe2x80x9c(C1-C6)alkylxe2x80x9d is as defined above
Unless otherwise indicated, the term xe2x80x9c[(C6-C10)alkyl]-NHxe2x80x94HCxe2x95x90Nxe2x80x94xe2x80x9d refers to 
wherein the term xe2x80x9c(C6-C10)arylxe2x80x9d is as defined above.
Unless otherwise indicated, the term xe2x80x9c(C1-C9)heteroarylxe2x80x9d refers to aromatic or multicyclic ring functional groups wherein at least one ring functional groups is aromatic, wherein said aromatic or multicyclic ring functional groups contain one or more heteroatoms selected from the group consisting of O, S, and N. The (C1-C9)heteroaryl functional groups can also be optionally substituted by one or more oxo sub-functional groups. Examples of heteroaryl functional groups include, but not limited to, benzimidazoylyl, benzofuranyl, benzofurazanyl, 2H-1-benzopyranyl, benzothiadiazine, benzothiazinyl, benzothiazolyl, benzothiophenyl, benzoxazolyl, chromanyl, cinnolinyl, furazanyl, furopyridinyl, furyl, imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl and triazolyl, wherein said (C1-C10)heteroaryl functional group is optionally substituted on any atoms capable of forming an additional bond by one or two sub-functional groups independently selected from halo, xe2x80x94CN, xe2x80x94OH, (C1-C6)alkyl, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkyl-Oxe2x80x94 and (C3C8)cycloalkyl-Oxe2x80x94. The foregoing (C1-C9)heteroaryls functional groups can be C-attached or N-attached where such is possible. For instance, pyrrolyl can be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).
Unless otherwise indicated, the term xe2x80x9c(C1-C9)heterocyclylxe2x80x9d refers to a cyclic functional group containing 1 to 9 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of N, O, and S. The heterocyclyl ring functional groups can be optionally substituted where such is possible by oxo, xe2x80x94CN, xe2x80x94OH, (C1-C6)alkyl, perfluoro(C1-C6)alkyl, perfluoro(C1-C6)alkyl-Oxe2x80x94, (C1-C6)alkyl-Oxe2x80x94 and (C3-C8)cycloalkyl-Oxe2x80x94. Examples of the cyclic functional groups include, but not limited to, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]-heptanyl, azetidinyl, dihydrofuranyl, dihydropyranyl, dihydrothienyl, dioxanyl, 1,3-dioxolanyl, 1,4-dithianyl, hexahydroazepinyl, hexahydropyrimidine, imidazolidinyl, imidazolinyl, isoxazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, 2H-pyranyl, 4H-pyranyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, quinolizinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothienyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl or trithianyl. The foregoing heterocyclyl can be C-attached or N-attached where such is possible. For example, piperidinyl can be piperidin-1-yl (N-attached) or piperidin-4-yl (C-attached).
In a preferred embodiment of the process of the invention, said fluoride containing salt contains a cationic metal selected from the group consisting of lithium, sodium, potassium, cesium, magnesium, calcium, strontium, and barium, more preferably potassium or cesium.
In another preferred embodiment of the process of the invention, wherein said fluoride containing salt contains a cationic metal as defined above, 0.01 to 15 equivalents, preferably 1 to 10 equivalents, of said fluoride containing salt relative to the compound of the formula I is used.
Unless otherwise indicated, the term xe2x80x9cequivalentsxe2x80x9d refers to the number of moles of the fluoride containing salt relative to the number of moles of the compound of the formula I.
In another preferred embodiment of the process of the invention, wherein said fluoride containing salt contains a cationic metal as defined above, said process is performed at a temperature of about 5xc2x0 C. to about 40xc2x0 C., preferably about 10xc2x0 C. to about 30xc2x0 C.
In another preferred embodiment of the process of the invention, wherein said fluoride containing salt contains a cationic metal as defined above, said process is performed in the presence of a solvent selected from the group consisting of dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetone and acetonitrile.
In another preferred embodiment of the process of the invention, said fluoride containing salt is tetra(C1-C8)alkylammonium fluoride or (C1-C16)alkyltri(C1-C2)alkylammonium fluoride; more preferably tetrabutylammonium fluoride or cetyltrimethylammonium fluoride.
In another preferred embodiment of the process of the invention, wherein said fluoride containing salt is tetra(C1-C8)alkylammonium fluoride or (C1-C16)alkyltri(C1-C2)alkylammonium fluoride; about 0.05 to about 5 equivalents; preferably 0.1 to 2 equivalents, of said fluoride containing salt relative to the compound of the formula I is used.
In another preferred embodiment of the process of the invention, wherein said fluoride containing salt is tetra(C1-C8)alkylammonium fluoride or (C1-C16)alkyltri(C1-C2)alkylammonium fluoride; said process is performed at a temperature of about 10xc2x0 C. to about 100xc2x0 C.; preferably about 20xc2x0 C. to about 80xc2x0 C.
In another preferred embodiment of the process of the invention, wherein said fluoride containing salt is tetra(C1-C8)alkylammonium fluoride or (C1-C16)alkyltri(C1-C2)alkylammonium fluoride; said process is performed in the presence of a solvent selected from the group consisting of acetonitrile, dichloromethane, chloroform, tetrahydrofuran and dichloroethane; more preferably tetrahydrofuran.
In another embodiment of the process of the invention, R10 is a radical selected from the group consisting of halo, (C1-C6)alkyl-SO3xe2x80x94, (C6-C10)aryl-SO3xe2x80x94, (C1-C6)alkyl-SO2xe2x80x94, or (C6-C10)aryl-SO2xe2x80x94, wherein said (C1-C6)alkyl component of said (C1-C6)alkyl-SO3xe2x80x94(C1-C6)alkyl-SO2xe2x80x94 radicals is optionally substituted by one to six fluoro substituents; more preferably R10 is a radical selected from the group consisting of chloro, bromo, methyl-SO3xe2x80x94, phenyl-SO3xe2x80x94, methyl-SO2xe2x80x94, and phenyl-SO3xe2x80x94; most preferably R10 is chloro.
In another preferred embodiment of the process of the invention, R10 is CF3-SO3xe2x80x94or CF3CF2xe2x80x94SO3xe2x80x94.
In another embodiment of the process of the invention, in said compound of formula R3xe2x80x94H, R3 is a radical selected from the group consisting of 
wherein R7 is preferably a radical selected from the group consisting of (C1-C6)alkyl, (C6-C10)aryl, (C3-C8)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl; more preferably a radical selected from the group consisting of (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C1-C10)heterocyclyl; most preferably a radical selected from the group consisting of methyl, tert-butyl, cyclohexyl, cyclopentyl piperidinyl, and morpholinyl;
wherein each R7 (C1-C6)alkyl radicals may optionally be substituted on any carbon atom by one to three substituents per (C1-C6)alkyl components independently selected from the group consisting of (C3-C7)cycloalkyl, (C6-C10)aryl, (C1-C9)heteroaryl, and (C1-C10)heterocyclyl; preferably (C3-C7)cycloalkyl; more preferably cyclohexyl or cyclopentyl.
wherein each R7 (C6-C10)aryl, (C3-C8)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl ring radicals may optionally be substituted on any ring carbon atom by one to three substituents per ring independently selected from the group consisting of halo and (C1-C6)alkyl optionally substituted by one to four fluoro moieties;
wherein each of R7 (C3-C8)cycloalkyl and (C1-C10)heterocyclyl radicals may also optionally be substituted on any ring carbon atom by at least one (C1-C6)alkylidene substituent per ring.
In another embodiment of the process of the invention, in said compound of formula R3xe2x80x94H, R3 is 
wherein R7 is a radical selected from the group consisting of (C1-C6)alkyl, (C6-C10)aryl, (C3-C8)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl; preferably a radical selected from the group consisting of (C1-C6)alkyl, (C3-C8)cycloalkyl, and (C1-C10)heterocyclyl; more preferably a radical selected from the group consisting of methyl, tert-butyl, cyclohexyl, cyclopentyl, piperidinyl, and morpholinyl; and
R8 is a radical selected from the group consisting of H and (C1-C6)alkyl; preferably H;
wherein each of R7 or R8 (C1-C6)alkyl radicals may optionally be substituted on any carbon atom by one to three substituents per (C1-C6)alkyl radicals independently selected from the group consisting of halo and xe2x80x94OH;
wherein each of R7 (C6-C10)aryl, (C3-C8)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl ring radicals may optionally be substituted on any ring carbon atom by one to three (C1-C6)alkyl substituents per ring wherein each of said (C1-C6)alkyl substituents are optionally substituted by one to four fluoro moieties;
wherein each of R7 (C3-C8)cycloalkyl and (C1-C10)heterocyclyl radicals may also optionally be substituted on any ring carbon atom by at least one oxo or one (C1-C6)alkylidene substituent per ring.
In another embodiment of the process of the invention, in said compound of formula R3xe2x80x94H, R3 is 
wherein R7 and R8 are taken together with the nitrogen to which they are attached to form a 3- to 8-membered heterocyclic ring radical; preferably a 5- to 6-membered heterocyclic ring radical; more preferably piperidinyl and morpholinyl;
wherein said 3- to 8-membered heterocyclic ring radical may optionally contain at least one nitrogen or one oxygen heteroatom in addition to said nitrogen to which R7 and R8 are attached;
wherein said 3- to 8-membered heterocyclic ring radical made up of R7 and R8 may optionally be substituted on any ring carbon atom by one to three (C1-C6)alkyl; preferably methyl; substituents per ring.;
wherein said 3- to 8-membered heterocyclic ring radical made up of R7 and R8 may optionally be substituted on any ring carbon atom by at least one (C1-C6)alkylidene substituent per ring.
In another embodiment of the process of the invention, in said compound of formula R3xe2x80x94H, R3 is 
wherein R6 is preferably H or (C1-C6)alkyl;
R7 is a radical independently selected from the group consisting of (C1-C6)alkyl, (C6-C10)aryl, (C3-C8)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl; preferably a radical independently selected from the group consisting of (C1-C6)alkyl, (C6-C10)aryl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl; more preferably a radical independently selected from the group consisting of methyl, ethyl, isobutyl, tert-butyl, phenyl, tetrahydrofuranyl, piperazinyl, morpholinyl, azepanyl, piperidinyl, and triazolyl;
R8 is a radical independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, (C3-C8)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl; preferably a radical independently selected from the group consisting of H and (C1-C6)alkyl;
wherein each of R6, R7, or R8 (C1-C6)alkyl radicals may optionally be substituted on any carbon atom by one to three substituents per (C1-C6)alkyl radicals independently selected from the group consisting of halo, xe2x80x94OH, and (C1-C6)alkyl-Oxe2x80x94; preferably halo and methyl-O;
wherein each of R7 or R8 (C6-C10)aryl, (C3-C8)cycloalkyl, (C1-C10)heteroaryl and (C1-C10)heterocyclyl ring radicals may optionally be substituted on any ring carbon atom by one to three substituents per ring independently selected from the group consisting of halo, xe2x80x94OH and (C1-C6)alkyl optionally substituted by one to four fluoro moieties; preferably by one to three substituents per ring independently selected from the group consisting of chloro, bromo and methyl;
wherein each of R7 or R8 (C3-C8)cycloalkyl and (C1-C10)heterocyclyl radicals may also optionally be substituted on any ring carbon atom by at least one methylidene substituent per ring.
In an embodiment of the process of the invention, in said compound of formula R3xe2x80x94H, R3 is 
wherein R6 and R7 are taken together with the nitrogen or the oxygen to which they are attached to form a 3- to 8-membered heterocyclic ring radical; preferably a 5- to 6-membered heterocyclic ring radical; more preferably pyrazolidin-1-yl;
wherein said 3- to 8-membered heterocyclic ring radical may optionally contain at least one nitrogen or one oxygen heteroatom in addition to said nitrogen or said oxygen to which R6 and R7 are attached;
wherein said 3- to 8-membered heterocyclic ring radical made up of R6 and R7 may optionally be substituted on any ring carbon atom by one to three substituents per ring independently selected from the group consisting of halo, xe2x80x94OH, (C1-C6)alkyl-Oxe2x80x94, and (C1-C6)alkyl optionally substituted by one to four fluoro moieties;
wherein said 3- to 8-membered heterocyclic ring radical made up of R6 and R7 may optionally be substituted on any ring carbon atom by at least one oxo or one (C1-C6)alkylidene substituent per ring; more preferably one oxo substituent per ring.
In an embodiment of the process of the invention, in said compound of formula R3xe2x80x94H, R3is 
wherein R7 and R8 are taken together with the nitrogen to which they are attached to form a 3- to 8-membered heterocyclic ring radical; preferably a 5- to 6-membered heterocyclic ring radical; wherein said 3- to 8-membered heterocyclic ring radical may optionally contain at least one nitrogen or one oxygen heteroatom in addition to said nitrogen to which R7 and R8 are attached; preferably said 3- to 8-membered heterocyclic ring radical is selected from the group consisting of imidazolidin-1-yl, piperazin-1-yl, piperazin-1-yl, morpholin-4-yl, azepan-1-yl, piperidin-1-yl, and 1,3,4-triazol-1-yl;
wherein said 3- to 8-membered heterocyclic ring radical made up of R7 and R8 may optionally be substituted on any ring carbon atom by one to three (C1-C6)alkyl; preferably methyl; substituents per ring;
wherein said 3- to 8-membered heterocyclic ring radical made up of R7 and R8 may also optionally be substituted on any ring carbon atom by at least one oxo substituent per ring.
In another embodiment of the process of the invention, R2 is a radical selected from the group consisting of H, xe2x80x94NO2, xe2x80x94CN, and (C1-C6)alkyl optionally substituted by one xe2x80x94OH or by one to three fluoro substituents; preferably R2 is (C1-C6)alkyl optionally substituted by one xe2x80x94OH or by one to three fluoro substituents; more preferably R2 is xe2x80x94CF3 or xe2x80x94CHF2.
In another embodiment of the process of the invention, R2 is a radical selected from the group consisting of (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C6-C10)aryl, (C1-C9)heteroaryl, and (C1-C9)heterocyclyl.
In another embodiment of the process of the invention, R2 is a radical selected from the group consisting of (C1-C6)alkyl-Oxe2x80x94, (C3-C7)cycloalkyl-Oxe2x80x94, (C6-C10)aryl-Oxe2x80x94, (C1-C9)heteroaryl-Oxe2x80x94, and (C1-C9)heterocyclyl-Oxe2x80x94.
In another embodiment of the process of the invention, R2 is a radical selected from the group consisting of Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C3-C7)cycloalkyl-(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94, and (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94.
In another embodiment of the process of the invention, R2 is a radical selected from the group consisting of (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C3-C7)cycloalkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C9)heteroaryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C9)heterocyclyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94.
In another embodiment of the process of the invention, R2 is a radical selected from the group consisting of (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C3-C7)cycloalkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, and (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94.
In another embodiment of the process of the invention, R2 is a radical selected from the group consisting of (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C3-C7)cycloalkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, and (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94.
In another embodiment of the process of the invention, R2 is a radical selected from the group consisting of (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, [(C3-C7)cycloalkyl]2-Nxe2x80x94, [(C6-C10)aryl]-NHxe2x80x94, [(C6-C10)aryl]2-Nxe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl )-N]xe2x80x94, [(C1-C9)heteroaryl]-NHxe2x80x94, [(C1-C9)heteroaryl]2-Nxe2x80x94, [(C1-C9)heterocyclyl]-NHxe2x80x94, and [(C1-C9)heterocyclyl]2-Nxe2x80x94.
In another embodiment of the process of the invention, R2 is a radical selected from the group consisting of H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94.
In another embodiment of the process of the invention, R2 is a radical selected from the group consisting of [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C3-C7)cycloalkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C3-C7)cycloalkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10aryl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C9)heteroaryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C9)heteroaryl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C9)heterocyclyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Sxe2x80x94.
In a preferred embodiment of the process of the invention, the ring of the formula (R5)-A-(SOmR4) is of the formula 
wherein X is preferably  greater than CH and m is preferably 2.
In another embodiment of the process of the invention, the ring of the formula (R5)-A-(SOmR4) is of the formula 
wherein m is 0, 1 or 2, preferably m is 2.
In another preferred embodiment of the process of the invention, the ring of the formula (R5)-A-(SOmR4) is of the formula 
In another embodiment of the process of the invention, R1 is a radical selected from the group consisting of H, xe2x80x94NO2, and xe2x80x94CN, preferably R1 is xe2x80x94CN.
In another embodiment of the process of the invention, R1 is a radical selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkyl-SO2xe2x80x94, and (C6-C10)aryl-SO2xe2x80x94.
In another embodiment of the process of the invention, R1 is a radical selected from the group consisting of Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C9)heteroaryl-(Cxe2x95x90O)xe2x80x94, and (C1-C9)heterocyclyl-(Cxe2x95x90O)xe2x80x94.
In another embodiment of the process of the invention, R1 is a radical selected from the group consisting of H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, HOxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94.
In a preferred embodiment of the process of the invention, R4 is a radical selected from the group consisting of xe2x80x94NH2 and (C1-C6)alkyl optionally substituted by one to four xe2x80x94OH substituents; more preferably R4 is (C1-C6)alkyl optionally substituted by one xe2x80x94OH substituents; most preferably R4 is methyl or 2-hydroxyethyl.
In another embodiment of the process of the invention, R4 is (C1-C6)alkyl-NHxe2x80x94 or [(C1-C6)alkyl]2-Nxe2x80x94.
In another embodiment of the process of the invention, R4 is a radical selected from the group consisting of (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, [(C6-C10)aryl(C1-C6)alkyl]-(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, (C6-C10)aryl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, [(C1-C6)alkyl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94, and [(C6-C10)aryl]-NHxe2x80x94(Cxe2x95x90O)xe2x80x94NHxe2x80x94.
In another embodiment of the process of the invention, R4 is a radical selected from the group consisting of [(C1-C6)alkyl]-NHxe2x80x94HCxe2x95x90Nxe2x80x94, [C1-C6)alkyl]2Nxe2x80x94HCxe2x95x90Nxe2x80x94, and [(C6-C10)aryl]-NHxe2x80x94HCxe2x95x90Nxe2x80x94.
In another embodiment of the process of the invention, R5 is a radical selected from the group consisting of H, halo, xe2x80x94OH, and (C1-C6)alkyl optionally substituted by one to four fluoro substituents; preferably R5 is a radical selected from the group consisting of H, bromo, chloro, fluoro, CF3, and methyl; more preferably R5 is H.
In another embodiment of the process of the invention, R5 is a radical selected from the group consisting of (C1-C6)alkyl-Oxe2x80x94, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, and xe2x80x94CN.
In another embodiment of the process of the invention, R5 is a radical selected from the group consisting of Hxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-(Cxe2x95x90O)xe2x80x94Oxe2x80x94, HOxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Oxe2x80x94(Cxe2x95x90O)xe2x80x94.
In another embodiment of the process of the invention, R5 is selected from the group consisting of (C1-C6)alkyl-NHxe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94, (C3-C7)cycloalkyl-NHxe2x80x94, (C6-C10)aryl-NHxe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94, and (C1-C9)heteroaryl-NHxe2x80x94.
In another embodiment of the process of the invention, R5 is selected from the group consisting of H2Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-NHxe2x80x94(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]2-Nxe2x80x94(Cxe2x95x90O)xe2x80x94, (C6-C10)aryl-(Cxe2x95x90O)xe2x80x94, [(C1-C6)alkyl]-[((C6-C10)aryl)-N]xe2x80x94(Cxe2x95x90O)xe2x80x94, (C1-C6)alkyl-Oxe2x80x94NHxe2x80x94(Cxe2x95x90O)xe2x80x94, and (C1-C6)alkyl-Sxe2x80x94.
In a more preferred embodiment of the process of the invention, said fluoride containing salt contains a cationic metal selected from the group consisting of potassium and cesium; wherein 1 to 10 equivalents of said fluoride containing salt relative to the compound of the formula I is used; wherein said process is performed at a temperature of about 10xc2x0 C. to about 30xc2x0 C.; most preferably about at 25xc2x0 C.; wherein said process is performed in the presence of a solvent selected from the group consisting of dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetone and acetonitrile; most preferably dimethylsulfoxide; wherein R3 is a radical selected from the group consisting of 
wherein R6, R7, and R8 are as defined above.
In another more preferred embodiment of the process of the invention, said fluoride containing salt is tetrabutylammonium fluoride or cetyltrimethylammonium fluoride; wherein 0.1 to 2 equivalents of said fluoride containing salt relative to the compound of the formula I is used; wherein said process is performed at a temperature of about 20xc2x0 C. to about 80xc2x0 C.; most preferably at about 25xc2x0 C.; wherein said process is performed in the presence of a solvent selected from the group consisting of acetonitrile, dichloromethane, chloroform, tetrahydrofuran and dichloroethane; most preferably tetrahydrofuran; wherein R3 is a radical selected from the group consisting of 
wherein R6, R7, and R8 are as defined above.
Examples of specific preferred compounds of the formula I prepared by the process of the present invention are the following:
1-(5-Methanesulfonyl-pyridin-2-yl)-5-(4-methylene-cyclohexylmethoxy)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;
5-(2-Fluoro-benzylsulfanyl)-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;
6-[4-cyano-3-difluoromethyl-5-(3,5-cis-dimethyl-piperidin-1-yl)-pyrazol-1-yl]-pyridine-3-sulfonic acid amide;
6-[4-cyano-5-(2,2-dimethyl-propoxy)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid amide;
3-Difluoromethyl-5-(cis-2,6-dimethyl-morpholin-4-yl)-1-(5-methanesulfonyl-pyridin-2-yl)-1H-pyrazole-4-carbonitrile;
5-Cyclopentylamino-3-difluoromethyl-1-(4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile;
5-(Nxe2x80x2-Ethyl-Nxe2x80x2-methyl-hydrazino)-1-(5-methanesulfonyl-pyridin-2-yl )-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;
5-tert-Butoxyamino-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;
5-Azepan-1-yl-1-(5-methanesulfonyl-pyridin-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile;
6-[4-Cyano-5-(3,5-dimethyl-piperidin-1-yl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid acetyl-amide;
6-[4-Cyano-5-(3,5-dimethyl-piperidin-1-yl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid propionyl-amide;
6-[4-Cyano-5-(3,5-dimethyl-piperidin-1-yl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid isobutyryl-amide;
6-[4-Cyano-5-(3,5-dimethyl-piperidin-1-yl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid (2,2-dimethyl-propionyl)-amide;
6-[4-Cyano-5-(3,5-dimethyl-piperidin-1-yl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid (1,1-dimethyl)-ethoxycarbonyl-amide;
6-[4-Cyano-5-(3,5-dimethyl-piperidin-1-yl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid (3-methyl-butyryl)-amide;
6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid acetyl-amide;
6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid propionyl-amide;
6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid isobutyryl-amide;
6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid (2,2-dimethyl-propionyl)-amide;
6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid (1,1-dimethyl)-ethoxycarbonyl-amide;
6-[4-Cyano-5-(2,2-dimethyl-propylamino)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid (3-methyl-butyryl)-amide;
6-[4-Cyano-3-difluoromethyl-5-(2,6-cis-dimethyl-morpholin-4-yl)-pyrazol-1-yl]-pyridine-3-sulfonic acid acetyl-amide;
4-[4-Cyano-3-difluoromethyl-5-(2,6-dimethyl-morpholin-4-yl)-pyrazol-1-yl]-N-propionyl-benzenesulfonamide;
6-[4-Cyano-5-(2,6-dimethyl-morpholin-4-yl)-3-trifluoromethyl-pyrazol-1-yl]-pyridine-3-sulfonic acid isobutyryl-amide; and
5-Azepan-1-yl-1-(4-methanesulfonyl-phenyl)-3-trifluoromethyl-1H-pyrazole-4-carbonitrile; or
the pharmaceutically acceptable salts thereof.